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Molecular and Cellular Biology, November 2008, p. 6773-6784, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.00941-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA{triangledown}

William Kong,1,2 Hua Yang,1 Lili He,1 Jian-jun Zhao,1 Domenico Coppola,3 William S. Dalton,4 and Jin Q. Cheng1*

Departments of Molecular Oncology,1 Pathology,3 Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612,4 Department of Pathology and Cell Biology, College of Medicine, University of South Florida, Tampa, Florida 336122

Received 12 June 2008/ Returned for modification 1 August 2008/ Accepted 8 September 2008

Transforming growth factor β (TGF-β) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-β-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-β-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-β induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-β. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-β-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.

* Corresponding author. Mailing address: H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., SRB3, Tampa, FL 33612. Phone: (813) 745-6915. Fax: (813) 745-3829. E-mail: jin.cheng{at}moffitt.org

{triangledown} Published ahead of print on 15 September 2008.

Molecular and Cellular Biology, November 2008, p. 6773-6784, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.00941-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Kato, M., Arce, L., Natarajan, R. (2009). MicroRNAs and Their Role in Progressive Kidney Diseases. CJASN 4: 1255-1266 [Abstract] [Full Text]  


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